Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Biomarkers, Tumor; Brain Neoplasms; Cell Cycle Checkpoints; Colorectal Neoplasms; DNA Mismatch Repair; Disease-Free Survival; Female; Humans; Male; Middle Aged; Mutation; Neoplastic Syndromes, Hereditary; Programmed Cell Death 1 Receptor; T-Lymphocytes; Young Adult
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
Le, Dung T; Durham, Jennifer N; Smith, Kellie N; Wang, Hao; Bartlett, Bjarne R; Aulakh, Laveet K; Lu, Steve; Kemberling, Holly; Wilt, Cara; Luber, Brandon S; Wong, Fay; Azad, Nilofer S; Rucki, Agnieszka A; Laheru, Dan; Donehower, Ross; Zaheer, Atif; Fisher, George A; Crocenzi, Todd S; Lee, James J; Greten, Tim F; Duffy, Austin G; Ciombor, Kristen K; Eyring, Aleksandra D; Lam, Bao H; Joe, Andrew; Kang, S Peter; Holdhoff, Matthias; Danilova, Ludmila; Cope, Leslie; Meyer, Christian; Zhou, Shibin; Goldberg, Richard M; Armstrong, Deborah K; Bever, Katherine M; Fader, Amanda N; Taube, Janis; Housseau, Franck; Spetzler, David; Xiao, Nianqing; Pardoll, Drew M; Papadopoulos, Nickolas; Kinzler, Kenneth W; Eshleman, James R; Vogelstein, Bert; Anders, Robert A; and Diaz, Luis A, "Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade." (2017). Articles, Abstracts, and Reports. 1341.